Vitamin C and cancer: what can we conclude--1,609
patients and 33 years later?

Abstract:

In 1976 an article co-authored by Linus Pauling described that 100
terminal cancer patients treated with intravenous vitamin C, followed by
oral maintenance, lived four times longer than a control group of 1,000
patients who did not receive vitamin C. The study was strongly
criticized because the control group was very different from the group
treated with vitamin C. the latter were declared terminally ill much
sooner than the control group thus resulting in an artificially longer
survival for the vitamin C group. three double blind placebo controlled
randomized trials performed at Mayo Clinic using oral vitamin C for
cancer patients were negative. in a phase i-ii trial performed by
Riordan et al, none of 24 cancer patients treated with IV vitamin C
responded. At this point we don't have information as to which is
the actual plasma level of vitamin C that can produce tumor shrinkage.
We don't have consistent information either regarding what is the
clinical dose necessary to yield therapeutic plasma levels. in view of
this lack of data after trials which have included at least 1,591
patients over 33 years, we have to conclude that we still do not know
whether Vitamin C has any clinically significant antitumor activity. Nor
do we know which histological types of cancers, if any, are susceptible
to this agent. Finally, we don't know what the recommended dose of
Vitamin C is, if there is indeed such a dose, that can produce an
anti-tumor response. [P R Health Sci J 2010;3:215-217]

In 1976, Dr. Cameron, a Scottish physician, published in I
collaboration with Linus Pauling an article in the prestigious I journal
PNAS describing that 100 terminal cancer patients treated with
intravenous vitamin C for 10 days followed by oral maintenance, lived
four times longer than a control group of 1,000 patients who did not
receive vitamin C (1). The study was retrospective in nature but
nevertheless it stirred a great deal of excitement in many scientific
minds as well as in the lay public, some of which still persists.
However, the study was strongly criticized by Dr. William Dewys who
discovered that the control group was very different from the group
treated with vitamin C because the latter were declared terminally ill
much sooner than the control group (2). Because survival was measured
from the time the patients were declared terminally ill to the time when
they died, that resulted in an artificially longer survival for those
assigned to receive Vitamin C. Dr. DeWys noticed this bias when he
discovered that the time that elapsed from the diagnosis of cancer to
becoming terminally ill was shorter for patients receiving Vitamin C as
compared with controls when it should have been similar for both groups.

In order to verify these findings, Creagan et al. from the Mayo
Clinic, decided to investigate further this issue in a rigorous
double-blind randomized prospective study in which half the patients
received high doses of oral Vitamin C and the other half an oral
placebo. The patients were all terminal and had failed prior
chemotherapy. The results were published in 1979 in the New England
Journal of Medicine (3). The control group and the vitamin C group were
very comparable regarding age, performance status and other important
prognostic factors. Sixty patients were treated with Vitamin C
(experimental group) and 63 with placebo (control group). There was no
difference in survival between the two groups with survival curves
virtually overlapping. No difference was found either in relation to
symptomatic improvement, weight loss or performance status.

Although patients in Cameron's original study were similar to
those from the Mayo Clinic, Linus Pauling criticized the latter study,
alleging that the Mayo Clinic patients had received prior chemotherapy,
and thus their immune system was deficient. For this reason, Moertel et
al. from Mayo Clinic, decided to repeat the study limiting it to
patients who had not received prior chemotherapy. The results, published
in 1985, were equally poor (4). A third double-blind study conducted by
Tschetter et al. also arrived at similar conclusions (5).

In 1994 Robinson et al. published a study conducted in nude mice
transplanted with squamous cell carcinoma and treated with high doses of
intravenous Vitamin C. The findings were somewhat worrisome because they
showed that high doses stimulated the growth of these tumors and only
megadoses had an antitumor effect (6). For vitamin C to be effective,
the doses had to be so high that it was not certain whether they could
be achieved in humans without intolerable toxicity. However, Casciari et
al. in 2001 published results of a study (7) aimed at determining which
Vitamin C levels in blood were necessary to produce an antitumor effect
on colon cancer cells growing in vitro. They found that levels of 10
mM/L or higher were required for this purpose. To determine which doses
of vitamin C were needed to achieve such a level in blood, they studied
a single patient to whom they first administered 30 and later on 60 gm
of intravenous vitamin C. They found that a dose of 60 gm was capable
ofproducing a plasma level above 10 mM/L. In a more recent dose finding
and pharmacokinetic phase I clinical trial (8), Hoffer et al. entered 18
patients with advanced cancer. The aim of that study was to explore the
safety of i.v. ascorbic acid administered in a dose sufficient to
sustain plasma ascorbic acid concentrations >10 mmol/l for several
hours. Pharmacokinetic studies were obtained for six patients infused
with 0.1, 0.2, 0.4, 0.6 and 0.9 g/kg and five patients infused with 1.5
g/kg. They determined that intravenous ascorbic acid, administered at a
dose of 1.5 g/kg three times weekly, appears to be safe and is capable
of achieving plasma ascorbic acid concentrations >10 mM/L for >4 h
in patients with normal renal function. They recommend a dose of 1.5
g/kg for future phase II trials. No antitumor response was observed in
these 18 patients.

The latter study aimed at obtaining plasma ascorbic acid
concentrations >10 mM/L for several hours since that appeared to be
the required concentration to attain antitumor effects. However, in
another study performed by Casciari et al. in guinea pigs, they found
that a much lower plasma level of 1 mM/L was capable of inducing
antitumor effects in L-10 transplanted cells (9). The quality of this
research study has to be questioned in view of the fact that essential
information such as the number of guinea pigs in each experiment was
missing from their report.

Based on the first study by Casciari (7), Riordan et al. criticized
the Mayo Clinic studies arguing that treatment with oral vitamin C can
not achieve the plasma levels of 10 mM/L required for the antitumor
effect of Vitamin C. According to him, only doses of 50 gm or higher
(equivalent to ~0.7 gm/kg in an average adult) are capable of achieving
such a plasma level. He chose to ignore the second study by Casciari in
which L10 tumor cells (9) were sensitive to much lower levels of Vitamin
C. Riordan ignored this study in spite of the fact that he had actually
co-authored that study with Casciari. Riordan then decided to administer
high doses of vitamin C intravenously to 24 patients with terminal
cancer (10). As it was unknown whether high doses could be tolerated
intravenously, they started treatment at a dose of 10 grams and
gradually escalated the doses to reach 50 grams. The drug was given as a
continuous infusion over 8 weeks. In general, these doses were well
tolerated except for one case who developed renal calculi and two who
developed anemia. It was disappointing that none of the 24 cancer
patients responded to treatment (10). The mean plasma level was 1.1 mM/L
which is in the range of the necessary therapeutic levels according to
the L-10 study (9) although below the range of 10 mM/L thought to be
necessary in the colon cancer in vitro model (7). It is very
disconcerting to find that the vitamin C levels in Riordan's
clinical trial in patients with cancer didn't correlate with the
dose administered (10). No explanation was given for this unusual
finding. Another unknown piece of information is what is the
intratumoral vitamin C level necessary to achieve cytotoxicity. It is
possible that malignant tumors might be more avid for vitamin C than
normal tissues and that a relatively low plasma level might be enough to
produce cytotoxicity. In fact that is exactly what Casciari's study
with the L-10 model showed. Most patients in Riordan's clinical
study were treated at doses below 50 gm and therefore according to him,
did not receive optimal treatment. Five patients did receive treatment
at the 50 gm dose and all of them failed to respond.

In conclusion, assuming that 1.5 g/kg three times weekly of
intravenous vitamin C is the recommended dose, then this agent has not
received a fair and adequate trial. However, we have contradictory
information as to which is the actual dose that can produce tumor
shrinkage. It is very likely that such dose might vary according to the
type of tumor treated.

After trials which have included at least 1,609 patients over 33
years, we have to conclude that we still do not know whether Vitamin C
has any clinically significant antitumor activity. Nor do we know which
histological types of cancers, if any, are susceptible to this agent.
Neither do we know with certainty what is the required plasma ascorbic
acid level that will result in antitumor effects. Assuming that this
level is 10 mM/L then the recommended dose of Vitamin C appears to be in
the range of 1.5 g/kg three times weekly.

Dr. Riordan's followers and collaborators, now close to 5
years after his death, have failed to generate convincing scientific
evidence that this drug is clinically effective. They should concentrate
their efforts in answering all of these so far unanswered questions.
From the clinical standpoint, a phase II study using 1.5 g/kg three
times weekly would be in order so as to establish if there is any hint
of antitumor activity. Clearly high dose intravenous Vitamin C is not
without its side effects, some of which can be very serious, including
renal failure (11-12). At this time it is not acceptable or ethical to
recommend this treatment to anyone with cancer, except within the
framework of a clinical trial.